Role of ROBO4 Signalling in Developmental and Pathological Angiogenesis

Figure 3

A schematic representation of SLIT/ROBO signalling during angiogenesis: SLIT2-ROBO4 signaling inhibits activation of Src and Rac1 to block VEGF driven angiogenesis and vascular permeability, while SLIT2 interacts with ROBO1 and transmits the signal through ROBO1–ROBO4 heterodimer formation. This inhibition is also mediated by binding and signaling through UNC5B where ROBO4 acts as ligand for UNC5B. On the other hand, the heterodimer formation prevents the recruited VILSE to CC2 domain of ROBO4 resulting in increased level of intracellular active CDC42-GTP and IRSp53. CDC42-GTP level can also be increased by hypoxia. The CDC42-GTP binds to CRIB domain of IRSp53 which releases the autoinhibitory effect of IRSp53 and allows the binding of MENA to SH3 domain of IRSp53. MENA recruits the complex to CC2 domain of ROBO4’s cytoplasmic region or directly mediates actin nucleation resulting in filopodia formation and directional migration promoting the angiogenesis.